DESCRIPTION (Abstract of the application) Currently, a rate limiting step to-the emerging field of gene therapy has been inefficient vector transduction. While many advances have been made in the development of various delivery systems, including retrovirus, adenovirus, herpes virus, adeno-associated virus (AAV), lenti virus, and non-viral vectors, these systems still lack the efficiency required for successful delivery in vivo. Furthermore, it will be critical to target viral vectors to specific cell types, and to dividing as well as non-dividing cells, for successful gene therapy. Along with modifying vectors for specific cell targeting, it will be essential to maintain proper endocytosis along with improved efficiency. In the proposed work we will explore the use of the small parvovirus, AAV, as a cell-specific targeting vector by manipulating the viral capsid proteins. Since the AAV virion is composed of only 3 capsid proteins encoded by overlapping reading frames, it should provide a simple system for genetic manipulation. The goal of this research is to identify and alter the region(s) of AAV capsid(s) that govern(s) its normal host range and to identify a region(s) that can be manipulated to display foreign epitopes on the surface of the capsid. Ultimately, these genetically modified capsid vectors will be tested for directed gene delivery in cultured cells with the long range goal of efficient targeted delivery in vivo.